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Backbone modified oligonucleotide analogues

a technology of backbone and oligonucleotide, which is applied in the direction of sugar derivates, esterified saccharide compounds, organic chemistry, etc., can solve the problem that the material is no longer a true nucleic acid species

Inactive Publication Date: 2005-05-31
IONIS PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

This patent describes a new type of antisense oligonucleotide analog that can be used to control the activity of RNA or DNA. These analogues molecules have been modified to have specific properties that make them more effective in entering cells and resistant to enzymes that break them down. They can be designed to target specific parts of RNA or DNA and can be used in therapeutics or research reagents. The patent also describes a method for synthesizing these analogues molecules using solid state synthetic methods. Overall, this patent provides a way to create new and improved tools for controlling gene expression.

Problems solved by technology

Moreover, when other substitutions, such a substitution for the inter-sugar phosphorodiester linkage are made, the resulting material is no longer a true nucleic acid species.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

example 1

Synthesis of CPG-bound Nucleosides for methylenehydrazine, i.e. (3′-CR2—NH—NH—CH2-5′), Linked Oligonucleoside

Diphenylimidazolidino Protected 5′-aldehydic thymidine

[0092]CPG-bound thymidine (30 micromoles of thymidine on one gram of CPG support, ABI, Foster City, Calif.) is treated at ambient temperature with a mixture of DMSO, benzene, DCC, pyridine, and trifluoroacetic acid (15 ml / 15 ml / 2.48 g / 0.4 ml / 0.2 ml in a procedure similar to the oxidation procedure of Pfitzer, K. E. and J. G. Moffatt, Journal of American Chemical Society 85:3027 (1963), to provide the 5′-aldehydic nucleoside. The mixture is filtered after storing overnight. The support is washed with oxalic acid (1.3 g in 5 ml benzene / DMSO, 1 to 1) and treated with 1,2-dianilinoethylene (3.0 g) for one hour, filtered, and washed with acetonitrile to afford the 5′-diphenylimidazolidino protected 5′-aldehydic thymidine.

5′-Deoxy-5′-hydrazino-thymidine

[0093]Treatment of the support-bound 5′-aldehydo thymidine with a solution of...

example 2

Synthesis of Uniform (3′-CH2—NH—NH—CH2-5′), i.e. methylenehydrazine, Linked Oligonucleosides on a DNA Synthesizer

[0095]CPG-bound thymidine with a diphenylimidazolidino protected 5′-aldehyde from Example 1 that will become the 3′-terminal nucleoside is placed in an Applied Biosystems, Inc. (ABI) column (250 mg, 10 micromoles of bound nucleoside) and attached to an ABI 380B automated DNA Synthesizer. The automated (computer controlled) steps of a cycle that are required to couple a desmethyl nucleoside unit to the growing chain are as follows.

[0096]

STEPREAGENT OR SOLVENT MIXTURETIME (min:sec)13% DCA in dichloroethane3:002Dichloroethane wash1:3035′-Deoxy-5′-(1,3-diphenylimidazolidino)-3′-deoxy-3′-C-methylene hydrazinenucleoside (the second nucleoside);20 micromoles in 30 ml of acetonitrile2:504Sodium borohydride (50 micromole in1:1 THF / EtOH, 50 ml)3:005Dichloroethane wash2:006Recycle starting at step 1 (acid wash)3:00

This procedure yields as its product nucleoside the 5′-dimethyoxytrit...

example 3

Synthesis of 5′-deoxy-5′-hydrazino Nucleosides

5′-Deoxy-5′-hydrazinothymidine hydrochloride

[0098]To provide 5′-benzylcarbazyl-5′-deoxythymidine, 5′-O-tosylthymidine, [Nucleosides &Nucleotides 9:89 (1990)] (1.98 g, 5 mmol), benzylcarbazide (4.15 g, 25 mmol), activated molecular sieves (3A, 2 g), and anhydrous dimethylacetamide (100 ml) were stirred together with exclusion of moisture at 110° C. (bath temperature) for 16 hours. The products were cooled and concentrated under reduced pressure (bath temperature 2Cl2 / MeOH (9:1, v / v) as the solvent. The homogeneous fractions were pooled, evaporated to dryness and the foam recrystallized from EtOH to yield 0.7 g (36%) of 5′-benzylcarbazyl-5′-deoxythymidine; mp 201° C.; 1H NMR (Me2SO-d6) δ 1.79 (s, 3, CH3), 2.00-2.18 (m, 2, C2,CH2), 2.95 (t, 2, C5,CH2), 3.75 (m, 1, C4,H), 4.18 (m, 1, C3,H), 4.7 (brs, 1, O′2NH), 5.03 (s, 2, PhCH2), 5.2 (d, 1, C3,H), 6.16 (t, 1, C1,H), 7.2-7.4 (m, 5, C6H5), 7.6 (s, 1, C6H), 8.7 (brs, 1, CH2NH), 11.2 (brs, 1, C...

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Abstract

Therapeutic oligonucleotide analogues which have improved nuclease resistance and improved cellular uptake are provided. Replacement of the normal phosphorodiester inter-sugar linkages found in natural oligomers with four atom linking groups forms unique di- and poly-nucleosides and nucleotides useful in regulating RNA expression and in therapeutics. Methods of synthesis and use are also disclosed.

Description

CROSS REFERENCE TO RELATED APPLICATIONS[0001]This application is a continuation of Ser. No. 09 / 058,470, filed Apr. 10, 1998 now abandoned which in turn is a divisional of Ser. No. 08 / 763,354 (now U.S. Pat. No. 5,965,721) filed Dec. 11, 1996 which is a divisional of Ser. No. 08 / 150,079 (now U.S. Pat. No. 5,610,289) file Apr. 7, 1994 which is a 371 of PCT / US92 / 04294, filed May 21, 1992 which is a continuation-in-part of Ser. No. 07 / 703,619 (now U.S. Pat. No. 5,378,825) filed May 21, 1991 which is a continuation-in-part of Ser. No. 07 / 566,836 (now U.S. Pat. No. 5,223,618) filed Aug. 13, 1990 which is a continuation-in-part of Ser. No. 07 / 558,663 (now U.S. Pat. No. 5,138,045) filed Jul. 27, 1990), the entirety of which is incorporated herein by reference.FIELD OF THE INVENTION[0002]This invention relates to the design, synthesis and application of nuclease resistant oligonucleotide analogues which are useful for therapeutics, diagnostics and as research reagents. Oligonucleotide analogu...

Claims

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Application Information

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Patent Type & Authority Patents(United States)
IPC IPC(8): A61K49/00A61K47/48C07D405/00C07D405/04C07D405/14C07H19/16C07H21/00C07H19/10C07F7/18C07F7/00C07H19/00C07H19/06C07H19/04
CPCA61K47/48192A61K49/0006C07D405/04C07D405/14C07F7/1856C07H21/00C07H19/04C07H19/06C07H19/10C07H19/16C07H11/00C07H19/073C07H21/02C07H21/04A61K47/59C07F7/1804
Inventor COOK, PHILLIP DANSANGHVI, YOGESH SHANTILALVASSEUR, JEAN JACQUESDEBART, FRANCOISE
Owner IONIS PHARMA INC
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